Platelet rich plasma and plasma rich in growth factors for split-thickness skin graft donor site treatment in the burn patient setting: A randomized clinical trial.

INTRODUCTION: Management of donor site morbidity in the setting of split thickness skin graft (STSG) is of crucial importance with no superior wound dressing described to date and the growing need of decreasing epithelializing time. The purpose of the study was to compare the standard of care using a hydrocolloid dressing to platelet rich plasma (PRP) and plasma rich in growth factors (PRGF) in order to determine its therapeutic potential in this setting. METHODS: A randomized clinical trial was conducted in which each patient served as its own control. PRGF was obtained by means of freeze-thaw out of the PRP from the subject of the study. Patients from the study had three donor sites and each donor site received either to PRP, PRGF or the standard of care, hydrocolloid. The main variable was time to epithelialization, and secondary variables subject to study were pain, quality of the scar, complications and cost. RESULTS: 20 patients were recruited with a total number of 60 donor sites to study. On the 8th post-operative day 55% and 45% of the sites treated with PRP and PRGF, respectively, complete epithelialization was observed as compared to 20% of the sites treated with hydrocolloid, statistical significance was achieved between the latter two (p = 0.036). The areas treated with PRP and PRGF received inferior values on the visual analog scale on post-op day 5 and 8 compared to hydrocolloid. Values on wound healing metrics were lower in the PRP when compared to hydrocolloid. No adverse effects were recorded. CONCLUSION: Donor site of STSG treated with PRP in the setting of the burn patient decreased time to epithelialization. In our study a better pain control and in scar quality was observed in both, the PRP and PRGF group.

Autologous Fat Grafting with Percutaneous Fasciotomy and Reduction of the Nipple-Areolar Complex for the Correction of Tuberous Breast Deformity in Teenagers.

BACKGROUND: Tuberous breast deformity in the adolescent can be a source of anxiety and social isolation. Current techniques of implant placement and flap reconstruction are not always feasible in this population. OBJECTIVES: The authors evaluated the use of autologous fat grafting with percutaneous fasciotomy and reduction in the nipple-areolar complex for correction of tuberous breast deformity in teenagers. METHODS: A retrospective chart review was conducted for nine teenaged patients with tuberous breast deformity who received autologous fat grafting between January 2016 and December 2018. The recipient site was prepared with the use of percutaneous fasciotomies to release the constricted lower pole of the breast, lowering of the inframammary crease, and reduction in the nipple-areolar complex. Fat was harvested by conventional liposuction prior to injection through three designated sites located at the inframammary fold, anterior axillary line, and upper pole. Complications were recorded. RESULTS: Patients had an average age of 14.9 years at the time of surgery. An average of 1.8 filling sessions were required with a mean of 220 cc of fat injected per breast. Patients were followed for an average of 21 months postoperatively. No serious complications were noted. All patients reported satisfaction with their final outcomes. CONCLUSIONS: Autologous fat grafting in conjunction with percutaneous fasciotomy and reduction in the nipple-areolar complex is a safe and effective treatment of the tuberous breast deformity in teenage patients. It provides an esthetic result with minimal scarring and high satisfaction rates while eliminating the need for flaps or implants. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Secondary Leiomyosarcoma of the Lower Limb Following Uterine Smooth Muscle Tumor of Uncertain Malignant Potential.

INTRODUCTION: This report presents uterine smooth muscle tumors of uncertain malignant potential course with an unpredictable clinical behavior and late metastases. Metastases have been described to the humerus, lung, and peritoneum. CASE PRESENTATION: Hereby we present the case of a 71-year-old woman with a past surgical history of hysterectomy and bilateral adnexectomy due to a smooth muscle tumor of unknown malignant potential, who was evaluated 6 years later after the appearance of a mass in the proximal third of the right lower limb. The mass was diagnosed as a G1 epithelioid leiomyosarcoma and was surgically removed with immediate reconstruction with a tendinous transfer to the tibialis posterior muscle to maintain foot dorsiflexion. CONCLUSION: Patients diagnosed with smooth uterine muscle tumors of uncertain malignant potential should be closely followed up given the possibility of recurrence and late metastases, bearing in mind uncommon locations as well, such as the lower limb.

A microphysiological model of the bronchial airways reveals the interplay of mechanical and biochemical signals in bronchospasm.

In asthma, the contraction of the airway smooth muscle and the subsequent decrease in airflow involve a poorly understood set of mechanical and biochemical events. Organ-level and molecular-scale models of the airway are frequently based on purely mechanical or biochemical considerations and do not account for physiological mechanochemical couplings. Here, we present a microphysiological model of the airway that allows for the quantitative analysis of the interactions between mechanical and biochemical signals triggered by compressive stress on epithelial cells. We show that a mechanical stimulus mimicking a bronchospastic challenge triggers the marked contraction and delayed relaxation of airway smooth muscle, and that this is mediated by the discordant expression of cyclooxygenase genes in epithelial cells and regulated by the mechanosensor and transcriptional co-activator Yes-associated protein. A mathematical model of the intercellular feedback interactions recapitulates aspects of obstructive disease of the airways, which include pathognomonic features of severe difficult-to-treat asthma. The microphysiological model could be used to investigate the mechanisms of asthma pathogenesis and to develop therapeutic strategies that disrupt the positive feedback loop that leads to persistent airway constriction.

Cancer-selective nanoparticles for combinatorial siRNA delivery to primary human GBM in vitro and in vivo.

Novel treatments for glioblastoma (GBM) are urgently needed, particularly those which can simultaneously target GBM cells' ability to grow and migrate. Herein, we describe a synthetic, bioreducible, biodegradable polymer that can package and deliver hundreds of siRNA molecules into a single nanoparticle, facilitating combination therapy against multiple GBM-promoting targets. We demonstrate that siRNA delivery with these polymeric nanoparticles is cancer-selective, thereby avoiding potential side effects in healthy cells. We show that we can deliver siRNAs targeting several anti-GBM genes (Robo1, YAP1, NKCC1, EGFR, and survivin) simultaneously and within the same nanoparticles. Robo1 (roundabout homolog 1) siRNA delivery by biodegradable particles was found to trigger GBM cell death, as did non-viral delivery of NKCC1, EGFR, and survivin siRNA. Most importantly, combining several anti-GBM siRNAs into a nanoparticle formulation leads to high GBM cell death, reduces GBM migration in vitro, and reduces tumor burden over time following intratumoral administration. We show that certain genes, like survivin and EGFR, are important for GBM survival, while NKCC1, is more crucial for cancer cell migration. This represents a powerful platform technology with the potential to serve as a multimodal therapeutic for cancer.

Verteporfin-Loaded Polymeric Microparticles for Intratumoral Treatment of Brain Cancer.

Glioblastoma (GBMs) is the most common and aggressive type of primary brain tumor in adults with dismal prognosis despite radical surgical resection coupled with chemo- and radiotherapy. Recent studies have proposed the use of small-molecule inhibitors, including verteporfin (VP), to target oncogenic networks in cancers. Here we report efficient encapsulation of water-insoluble VP in poly(lactic- co-glycolic acid) microparticles (PLGA MP) of ∼1.5 µm in diameter that allows tunable, sustained release. Treatment with naked VP and released VP from PLGA MP decreased cell viability of patient-derived primary GBM cells in vitro by ∼70%. Moreover, naked VP treatment significantly increased radiosensitivity of GBM cells, thereby enhancing overall tumor cell killing ability by nearly 85%. Our in vivo study demonstrated that two intratumoral administrations of sustained slow-releasing VP-loaded PLGA MPs separated by two weeks significantly attenuated tumor growth by ∼67% in tumor volume in a subcutaneous patient-derived GBM xenograft model over 26 d. Additionally, our in vitro data indicate broader utility of VP for treatment for other solid cancers, including chordoma, malignant meningioma, and various noncentral nervous system-derived carcinomas. Collectively, our work suggests that the use of VP-loaded PLGA MP may be an effective local therapeutic strategy for a variety of solid cancers, including unresectable and orphan tumors, which may decrease tumor burden and ultimately improve patient prognosis.

Desbridamiento enzimático con Nexobrid® en el paciente quemado: exposición de manejo terapéutico a propósito de un caso / Desbridamento enzimático com Nexobrid® no paciente queimado: exposição do manejo terapêutico e relato de caso / Enzymatic debridement in the burn patient with Nexobrid®: exposition of therapeutic management and case report

Objetivo: Exponer el manejo terapéutico del desbridante enzimático Nexobrid® a través de un caso representativo. Reporte del caso: Se expone el caso de un paciente varón de 43 años que sufre quemaduras circulares de segundo grado profundo en ambas manos por flash eléctrico y llama, que fue tratado mediante desbridamiento enzimático con Nexobrid®, sin llegar a precisar de la realización de injertos cutáneos. Se alcanzó la epitelización completa de las lesiones 28 días tras la quemadura, sin realizarse injertos cutáneos, y logrando una buena calidad cicatricial, sin aparición de limitaciones funcionales. Consideraciones finales: El desbridamiento enzimático con Nexobrid® es un nuevo recurso terapéutico que permite realizar un desbridamiento completo y específico del tejido quemado, sin precisar de la logística de un quirófano. Pese a los buenos resultados reportados en la literatura reciente, los beneficios del uso del desbridante enzimático Nexobrid®, todavía han de ser respaldados por mayor cantidad de estudios con un adecuado nivel de evidencia.

Objetivo: Expor o manejo terapêutico do agente de debridamento enzimático Nexobrid® em um caso representativo. Relato de caso: Relatamos o caso de um homem de 43 anos com queimaduras profundas de segundo grau em ambas as mãos causadas por flash elétrico e chama, que foi tratada por desbridamento enzimático com Nexobrid®, sem a necessidade de enxerto de pele. Epitelização completa foi obtida 28 dias após a queimadura, sem a necessidade de realizar enxertos na pele, conseguindo uma boa qualidade da cicatriz, sem qualquer limitação funcional após 102 dias de seguimento. Considerações finais: O desbridamento enzimático com Nexobrid® é um novo recurso terapêutico que permite um desbridamento completo e específico de tecidos queimados, sem requerer a logística de uma cirurgia. Apesar dos bons resultados relatados na literatura recente, os benefícios deste tratamento devem ser respaldados por uma ampla gama de estudos com níveis adequados de evidência.

Objective: To expose the therapeutic management of the enzymatic debriding agent Nexobrid® through a representative case. Case report: We expose the case of a 43 year-old male suffering from circular deep second degree burns in both hands caused by electric flash and flame, who was treated through enzymatical debridement with Nexobrid®, without the need of skin grafting. Complete epithelialization was achieved 28 days after the burn, without the need to perform skin grafting, achieving good scar quality, without any functional limitation after 102 days follow-up. Final considerations: Enzymatical debridement with Nexobrid® is a new therapeutic resource which allows for a complete and specific debridement of burned tissues, without requiring the logistics of a surgery. Despite the good results reported in recent literature, the benefits of this treatment must be supported by a wider range of studies with adequate levels of evidence.

Effects of primary and recurrent sacral chordoma on the motor and nociceptive function of hindlimbs in rats: an orthotopic spine model.

OBJECTIVE Chordoma is a slow-growing, locally aggressive cancer that is minimally responsive to conventional chemotherapy and radiotherapy and has high local recurrence rates after resection. Currently, there are no rodent models of spinal chordoma. In the present study, the authors sought to develop and characterize an orthotopic model of human chordoma in an immunocompromised rat. METHODS Thirty-four immunocompromised rats were randomly allocated to 4 study groups; 22 of the 34 rats were engrafted in the lumbar spine with human chordoma. The groups were as follows: UCH1 tumor-engrafted (n = 11), JHC7 tumor-engrafted (n = 11), sham surgery (n = 6), and intact control (n = 6) rats. Neurological impairment of rats due to tumor growth was evaluated using open field and locomotion gait analysis; pain response was evaluated using mechanical or thermal paw stimulation. Cone beam CT (CBCT), MRI, and nanoScan PET/CT were performed to evaluate bony changes due to tumor growth. On Day 550, rats were killed and spines were processed for H & E-based histological examination and immunohistochemistry for brachyury, S100ß, and cytokeratin. RESULTS The spine tumors displayed typical chordoma morphology, that is, physaliferous cells filled with vacuolated cytoplasm of mucoid matrix. Brachyury immunoreactivity was confirmed by immunostaining, in which samples from tumor-engrafted rats showed a strong nuclear signal. Sclerotic lesions in the vertebral body of rats in the UCH1 and JHC7 groups were observed on CBCT. Tumor growth was confirmed using contrast-enhanced MRI. In UCH1 rats, large tumors were observed growing from the vertebral body. JHC7 chordoma-engrafted rats showed smaller tumors confined to the bone periphery compared with UCH1 chordoma-engrafted rats. Locomotion analysis showed a disruption in the normal gait pattern, with an increase in the step length and duration of the gait in tumor-engrafted rats. The distance traveled and the speed of rats in the open field test was significantly reduced in the UCH1 and JHC7 tumor-engrafted rats compared with controls. Nociceptive response to a mechanical stimulus showed a significant (p < 0.001) increase in the paw withdrawal threshold (mechanical hypalgesia). In contrast, the paw withdrawal response to a thermal stimulus decreased significantly (p < 0.05) in tumor-engrafted rats. CONCLUSIONS The authors developed an orthotopic human chordoma model in rats. Rats were followed for 550 days using imaging techniques, including MRI, CBCT, and nanoScan PET/CT, to evaluate lesion progression and bony integrity. Nociceptive evaluations and locomotion analysis were performed during follow-up. This model reproduces cardinal signs, such as locomotor and sensory deficits, similar to those observed clinically in human patients. To the authors' knowledge, this is the first spine rodent model of human chordoma. Its use and further study will be essential for pathophysiology research and the development of new therapeutic strategies.

Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents.

BACKGROUND CONTEXT: Metastases to the spine are a common source of severe pain in cancer patients. The secondary effects of spinal metastases include pain, bone fractures, hypercalcemia, and neurological deficits. As the disease progresses, pain severity can increase until it becomes refractory to medical treatments and leads to a decreased quality of life for patients. A key obstacle in the study of pain-induced spinal cancer is the lack of reliable and reproducible spine cancer animal models. In the present study, we developed a reproducible and reliable rat model of spinal cancer using human-derived tumor tissue to evaluate neurological decline using imaging and behavioral techniques. PURPOSE: The present study outlines the development and characterization of an orthotopic model of human breast cancer to the spine in immunocompromised rats. STUDY DESIGN/SETTING: This is a basic science study. METHODS: Female immunocompromised rats were randomized into three groups: tumor (n=8), RBC3 mammary adenocarcinoma tissue engrafted in the L5 vertebra body; sham (n=6), surgery performed but not tumor engrafted; and control (n=6), naive rats, no surgery performed. To evaluate the neurological impairment due to tumor invasion, functional assessment was done in all rodents at day 40 after tumor engraftment using locomotion gait analysis and pain response to a mechanical stimulus (Randall-Selitto test). Bioluminescence (BLI) was used to evaluate tumor growth in vivo and cone beam computed tomography (CBCT) was performed to evaluate bone changes due to tumor invasion. The animals were euthanized at day 45 and their spines were harvested and processed for hematoxylin and eosin (H&E) staining. RESULTS: Tumor growth in the spine was confirmed by BLI imaging and corroborated by histological analysis. Cone beam computed tomography images were characterized by a decrease in the bone intensity in the lumbar spine consistent with tumor location on BLI. On H&E staining of tumor-engrafted animals, there was a near-complete ablation of the ventral and posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups. CONCLUSIONS: We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis.

Postoperative Delayed Paradoxical Depression After Uncomplicated Unruptured Intracranial Aneurysm Surgery.

BACKGROUND: Postoperative delayed paradoxical depression (PDPD) is a psychiatric condition described in patients without a history of mood disorders who undergo major surgery without complications and become clinically depressed. PDPD has been recognized in major surgical interventions, including coronary artery bypass surgery. We sought to determine the incidence and potential factors associated with PDPD after surgical treatment of unruptured intracranial aneurysms. METHODS: The cohort of 105 patients was derived from a prospective observational data set of 3788 consecutive cases of intracranial aneurysms accrued from 1991 to 2015. Starting in 2010, patients with PDPD were identified, and psychiatric treatment and outcomes were documented. Incidence of PDPD and baseline characteristics were analyzed. Multivariate logistic regression was performed to analyze associations of variables with PDPD. Patients with preoperative depression or bipolar disorder were excluded. RESULTS: Of 105 patients, 10.5% (n = 11) were found to have newly diagnosed major depressive disorder after surgical treatment of intracranial aneurysms. By univariate and multivariate analysis, the only significant difference between the 2 groups was full return to daily activities (P = 0.017 and P = 0.029, odds ratio = 0.06, 95% confidence interval [0.00, 0.70]), which was a result and not a cause of PDPD. All 11 patients with PDPD recovered fully, 9 after psychotherapy and/or pharmacotherapy and 2 without intervention. CONCLUSIONS: PDPD after uncomplicated unruptured aneurysm surgery can be surprising to the neurosurgeon and the patient and should be promptly identified and addressed to achieve a full recovery. PDPD can be interpreted as a mild variant of post-traumatic stress disorder.

A Systematic Review of Metastatic Hepatocellular Carcinoma to the Spine.

BACKGROUND: Hepatocellular carcinoma (HCC) frequently metastasizes to the spine. The impact of medical and/or surgical intervention on overall survival has been examined in a limited number of clinical studies, and herein we systematically review these data. METHODS: We performed a literature review using PubMed, Embase, CINAHL, and Web of Science to identify articles that reported survival, clinical outcomes, and/or prognostic factors associated with patients diagnosed with spinal metastases. The methodologic quality of each review was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses tool. RESULTS: There were 26 articles (152 patients) that met the inclusion criteria and were treated with either surgery, radiotherapy, chemotherapy, and/or observation. There were 3 retrospective cohort studies, 17 case reports, 5 case series, and 1 longitudinal observational study. Of the patients with known overall survival after diagnosis of spinal metastasis, survival at 3 months, 6 months, 1 year, 2 years, and 5 years was 95.2%, 83.0%, 28.6%, 2.0%, and 1.4%, respectively. The median survival after diagnosis of the metastasis was 0.7 months in the patients who received no treatment, 7 months in the patients treated with surgical intervention alone, 6 months for patients who received chemotherapy and/or radiation, and 13.5 months in the patients treated with a combination of surgery and medical management. All other clinical or prognostic parameters were of low or insufficient strength. CONCLUSIONS: Patients diagnosed with HCC spinal metastasis have a 10.6-month overall survival. Further analysis of patients in prospective controlled trials will be essential to the development of treatment algorithms for these patients in the future.

Non-hepatocellular carcinoma spinal metastases.

Metastases to the spine from non-hepatocellular carcinomas, such as cholangiocarcinoma and angiosarcoma, occur rarely. With improvements in oncologic care, the number of patients diagnosed with metastatic cancer is expected to increase. We performed a systematic review of the literature to assess the clinical presentation, treatment, outcome and survival of patients diagnosed with non-hepatocellular carcinoma spinal metastasis using PubMed, Embase, CINAHL, Cochrane Library and Web of Science. We identified 19 cases of spinal metastases from non-hepatocellular carcinomas that fit our pre-specified criteria. The mean age at presentation was 62.3years and cholangiocarcinoma was the most common subtype. Patients frequently presented with pain, weakness or paraparesis and at the time of diagnosis, most of them had multi-level involvement of the spine. A majority of patients with spinal metastasis were treated either with radiation or chemotherapy or received no treatment. A minority of the reports included information on survival, which revealed a median survival of 1.5months following diagnosis of the spinal metastasis. Although there is a paucity of published literature on non-hepatocellular carcinoma spinal metastasis, this systematic review provides descriptive clinical characteristics of these patients.

Current standing and frontiers of gene therapy for meningiomas.

Meningiomas are among the most common intracranial tumors. The treatment of choice for these lesions is complete resection, but in 50% of cases it is not achieved due to tumor location and/or surgical morbidities. Moreover, benign meningiomas have high recurrence rates of up to 32% in long-term follow-up. Molecular analyses have begun to uncover the genetics behind meningiomas, giving rise to potential genetics-based treatments, including gene therapy. The authors performed a literature review on the most relevant genes associated with meningiomas and both current and potential gene therapy strategies to treat these tumors. Wild-type NF2 gene insertion, oncolytic viruses, and transfer of silencing RNA have all shown promising results both in vitro and in mice. These strategies have decreased meningioma cell growth, proliferation, and angiogenesis. However, no clinical trial has been done to date. Future research and trials in gene insertion, selective inhibition of oncogenes, and the use of oncolytic viruses, among other potential treatment approaches, may shape the future of meningioma management.